Vinca derivatives

Inactive Publication Date: 2008-05-22
ALBANY MOLECULAR RESEARCH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0081]Another aspect of the present invention relates to a process for

Problems solved by technology

The disruption of external or internal regulation of cellular growth can lead to uncontrolled cellular proliferation and in cancer, tumor formation.
Under these circumstances, although tumor cells can no longer control their own proliferation, such cells still must use the same basic cellular machinery employed by normal cells to drive their growth and replication.
For example, at low concentrations, these compounds interfere with the dynamics of microtubule formation.
Moreover, the anti-cancer activity of vinca alkaloids is generally believed to result from a disruption of microtubules resulting in mitotic arrest.
The assembly of tubulin into microtubules is a complex process involving dynamic instability (i.e. the switching between periods of slow growth and rapid shortening at both ends of the microtubule), and treadmilling (i.e. the addition of tubulin to one end of the microtubule occurring at the same rate as loss of tubulin from the other).
Although the spindle is retained under these conditions, there is frequently abnormal alignment of condensed chromosomes.
The vinca derivatives fall into the general class of cytotoxic anti-cancer agents and, as such, suffer from the same problem as all cytotoxics—i.e., toxicity.

Method used

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Examples

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example 1

Preparation of 3′,4′-Anhydrovinblastine (A)

[0409]This compound was prepared from vinblastine sulfate (3.7 g, 4.1 mmol) according to a reported procedure with slight modifications (Bull. Soc. Chim Belg. 92:485 (1983), which is hereby incorporated by reference in its entirety). The crude product (3.0 g; a yellow solid) was used in the next step without purification: ESI MS m / z 793 [M+H]+.

example 2

Preparation of 4′-Deoxy-20′, 20′-difluorovinblastine (B)

[0410]This compound was prepared from 3′,4′-anhydrovinblastine (A; crude, 3.0 g) according to a reported procedure with slight modifications (U.S. Pat. No. 6,127,377, which is hereby incorporated by reference in its entirety), the spectral data of which were consistent with those reported therein (0.90 g, 26% over two steps).

example 3

Preparation of 4′-Deoxy-20′, 20′-difluoro-12′-iodovinblastine (2)

[0411]4′-Deoxy-20′, 20′-difluorovinblastine (B; 300 mg, 0.36 mmol) was dissolved in MeCN (2 mL) and cooled to −15° C. Then conc. H2SO4 (0.30 mL) was added dropwise at −15° C. followed by dropwise addition of NIS (81 mg, 0.36 mmol) in MeCN (1 mL) at −10˜−15° C. The reaction mixture was stirred at −15˜−10° C. for 2 h, quenched with saturated NaHCO3 (10 mL) and extracted with EtOAc (3×10 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated to give the crude title compound as a brown-yellow solid, which was used in the next step without purification.

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Abstract

The present invention relates to derivatives of vinca alkaloids. Pharmaceutical compositions containing these compounds as well as processes of preparation and treatment of various conditions are also disclosed.

Description

[0001]The present invention claims benefit of U.S. Provisional Application Ser. No. 60 / 843,975, filed Sep. 12, 2006, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to derivatives of the vinca alkaloids which are potent inhibitors of cellular mitosis and proliferation, as well as pharmaceutical compositions, preparation processes, and methods of use for treatment of various conditions.BACKGROUND OF THE INVENTIONCellular Proliferation and Cancer[0003]The disruption of external or internal regulation of cellular growth can lead to uncontrolled cellular proliferation and in cancer, tumor formation. This loss of cellular growth control can occur at many levels and, indeed, does occur at multiple levels in most tumors. Under these circumstances, although tumor cells can no longer control their own proliferation, such cells still must use the same basic cellular machinery employed by normal cells to drive their growth and...

Claims

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Application Information

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IPC IPC(8): A61K31/437C07D471/16A61P35/00
CPCC07D519/00A61P35/00
InventorWOLF, MARK A.GUZZO, PETER R.SCOTT, IAN L.
OwnerALBANY MOLECULAR RESEARCH INC